Hetaryloxy-β-carbolines, their production and use in pharmaceutical agents

ABSTRACT

Hetaryloxy- beta -carbolines of formula I   &lt;IMAGE&gt;   in which RA means a triazine or benzocondensed hetaryl radical with 1-2 nitrogen atoms optionally substituted with halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, trifluoromethyl or SO2-R1 or a 5- or 6-membered hetaryl radical with 1-2 nitrogen atoms substituted with halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, trifluoromethyl or SO2-R1 are useful pharmaceutical agents.

This is a division of application Ser. No. 07/892,819, filed Jun. 5,1992 now U.S. Pat. No. 5,348,958.

SUMMARY OF THE INVENTION

The invention relates to new hetaryloxy-β-carboline derivatives, theirproduction and use in pharmaceutical agents.

In EP-A-237 467 and EP-A-305 322, β-carbolines substituted with ahetaryloxy radical are described, which influence the central nervoussystem and are used as psychopharmaceutical agents. According to thesepatent applications, it was not to be expected that with theintroduction of the hetaryl substituents according to the invention, adisplacement of the active profile of the compounds takes place and thatthe compounds show an improved side effect profile because of the absentmuscular relaxation.

The compounds according to the invention have formula I ##STR2## inwhich R^(A) means a triazine or benzocondensed hetaryl radical with 1-2nitrogen atoms optionally substituted with halogen, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ alkylthio, trifluoromethyl or SO₂ --R¹ or represents a 5-or 6-membered hetaryl radical with 1-2 nitrogen atoms substituted withhalogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, trifluoromethyl or--SO₂ --R¹, and R¹ is C₁₋₄ alkyl or phenyl optionally substituted 1-2times with C₁₋₄ alkyl and R^(A) can be substituted once to twice, andthe substituent is not halogen, if R^(A) means pyridine,

R⁴ means hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₂ alkyl and

R³ means --CO₂ --C₁₋₆ alkyl, --CO--R², --CO₂ H, ##STR3## and R² meansC₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₇₋₉ bicycloalkyl or a monocyclic orbicyclic C₆₋₁₂ aryl radical optionally substituted with C₁₋₄ alkyl, C₁₋₄alkoxy or amino,

R^(a) and R^(b) are the same or different and respectively meanhydrogen, C₁₋₆ alkoxy, C₁₋₆ alkyl, --CH₂ --O--C₁₋₄ alkyl, phenyl orbenzyl,

R^(c) and R^(d) respectively mean hydrogen or together a bond and

R⁵ is hydrogen, C₁₋₄ alkyl or C₃₋₇ cycloalkyl, as well as their isomersand acid addition salts.

Substituent R^(A) can be in position 5-8 of the A-ring, preferably in5-, 6- or 7-position.

Alkyl portions are both straight-chain and branched-chain radicals, suchas, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, isopentyl and hexyl.

Halogens are fluorine, chlorine, bromine and iodine.

Cycloalkyl groups are, for example, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or cycloheptyl.

As benzocondensed hetaryl radicals with 1-2 nitrogen atoms, there are,for example, quinoline, isoquinoline, quinoxaline, benzimidazo.Generally, these have 2 rings each of which can be a 4-, 5- or6-membered ring, there being generally about 8-12 ring atoms in total.

Substituted nitrogen-containing hetaryl radicals, for example, includepyridine, pyrimidine, pyrazine, pyridazine, imidazole, etc.

Suitable bicycloalkyl radicals R² are bicycloheptyl and bicyclooctyl.Suitable monocyclic or bicyclic aryl radicals R² are, for example,phenyl, biphenyl, naphthyl and indenyl.

The number of substituents on the hetaryl radicals R^(A) on phenylradical R¹ and on aryl radical R² can be one or two and can be in anyposition.

Preferred embodiments for R^(A) include quinoline, isoquinoline orquinoxaline each optionally substituted with halogen, C₁₋₆ alkyl or C₁₋₆alkoxy, triazine optionally substituted once to twice with halogen, C₁₋₆alkyl, C₁₋₆ alkoxy or C₁₋₆ alkylthio or pyridine, pyrimidine, pyrazineor pyridazine radicals each substituted with C₁₋₆ alkyl, C₁₋₆ alkoxyC₁₋₆ alkylthio, trifluoromethyl or SO₂ --R¹, or pyrimidine, pyridazineor pyrazine each substituted with halogen.

For R³, --CO₂ --C₁₋₆ alkyl, --CO--R² wherein R² is a C₃₋₇ cycloalkyl oran optionally substituted phenyl radical or isoxazol-3-yl radical arepreferred.

The physiologically compatible acid addition salts are derived from theknown inorganic and organic acids, such as, for example, hydrochloricacid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid,acetic acid, benzoic acid, maleic acid, fumaric acid, succinic acid,tartaric acid, citric acid, oxalic acid, glyoxylic acid as well as fromalkanesulfonic acids, such as, for example, methanesulfonic acid,ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, amongothers.

The compounds of formula I as well as their acid addition salts can beused as pharmaceutical agents because of their affinity tobenzodiazepine receptors. They have a partial agonistic effect on theproperties known for the benzodiazepines, which is characterized in thatthe compounds, for example, have an anticonvulsive and anxiolytic effectand are not atactic/muscle-relaxing. To test the anxiolytic effect, thecompounds can be tested in the 4-plate test according to the method ofBoissier et al., Eur. J. Pharmacol. 4, 145-150 (1968). In the table, theminimal effective dose (MED) is indicated, which increases the locomotoractivity of the afflicted mice after i.p. treatment.

                  TABLE                                                           ______________________________________                                        Compound      MED mg/kg i.p.                                                  ______________________________________                                        A             1.56                                                            B             0.39                                                            ______________________________________                                         A = 6(1-isoquinolyloxy)-4-methoxymethyl-carboline-3-carboxylic                acidisopropyl ester                                                           B =                                                                           6(2,6-dimethoxy-4-pyrimidinyloxy)-4-methoxymethyl-carboline-3-carboxylic      acidisopropyl ester                                                      

Because of the good effectiveness in the PTZ convulsion test and in the4-plate test, the compounds according to the invention are suitableespecially for treatment of epilepsy and anxiety.

To use the compounds according to the invention as pharmaceuticalagents, the latter are brought into the form of a pharmaceuticalpreparation, which in addition to the active ingredient for enteral orparenteral administration contains suitable pharmaceutical, organic orinorganic inert vehicles, such as, for example, water, gelatin, gumarabic, lactose, starch, magnesium stearate, talc, vegetable oils,polyalkylene glycols, etc.

The pharmaceutical preparations can be present in solid form, forexample, as tablets, coated tablets, suppositories, capsules or inliquid form, for example, as solutions, suspensions or emulsions. Theyfurther optionally contain auxiliary agents such as preservatives,stabilizers, wetting agents or emulsifiers, salts to change the osmoticpressure or buffers.

For parenteral use, especially injection solutions or suspensions,especially aqueous solutions of the active compounds inpolyhydroxyethoxylated castor oil, are suitable.

As vehicle systems, surface-active auxiliary agents such as salts ofbile acids or animal or vegetable phospholipids but also their mixturesas well as liposomes or their components can also be used.

For oral use, tablets, coated tablets or capsules with talc and/orhydrocarbon vehicles or binding agents, such as, for example, lactose,corn or potato starch, are especially suitable. The use can also takeplace in liquid form, such as, for example, as juice, to which asweetener optionally is added.

The compounds according to the invention can be used in a dosage unit of0.05 to 100 mg of active substance in a physiologically compatiblevehicle.

The compounds according to the invention are generally used in a dose of0.1 to 300 mg/day, preferably 0.1 to 30 mg/day, especially preferably1-20 mg/day, for example as anxiolytic agents analogous to diazepam.

The production of the compounds according to the invention takes placeaccording to methods known in the art. For example, compounds of formulaI are attained in that

a) compounds of formula II ##STR4## in which R⁴ and R³ have theabove-named meaning, with R^(A) Y, in which R^(A) has the above-namedmeaning and Y is halogen or a reactive group, are etherified or

b) compounds of formula III ##STR5## in which R⁴ has the above-namedmeaning, R^(A') is hydrogen or R^(A) and Z is hydrogen, C₁₋₄ alkoxy or areactive acid derivative, are reacted with a lithium-organic compound,optionally after introducing a protecting group in 9-position tocompounds of formula I with R³ =--CO--R² or

c) compounds of formula IV ##STR6## in which R^(A') is hydrogen or R^(A)and R⁴ has the above-named meaning, are cyclized with a compound offormula V ##STR7## in which R^(a), R^(b), R^(c), and R^(d) have theabove-named meaning, to compounds of formula I with R³ meaning ##STR8##

d) compounds of formula VI ##STR9## in which R^(A') is hydrogen or R^(A)and R⁴, R^(a), R^(c) and R^(d) have the above-named meaning, arecyclized with a nitrile oxide of formula VII

    R.sup.b --C.tbd.N.sup.+ --O.sup.-                          VII,

in which R^(b) has the above-named meaning, to compounds of formula Iwith R³ meaning ##STR10## or

e) compounds of formula VIII ##STR11## in which R^(A') is hydrogen orR^(A) and R⁴ has the above-named meaning, are cyclized with a compoundof formula (R⁵ CO)₂ O with R⁵ in the above-named meaning to compoundswith R³ meaning ##STR12## or

f) compounds of formula IX ##STR13## in which R^(A') is hydrogen orR^(A), R⁴ has the above-named meaning and R⁶ means OH or a reactive acidderivative, are reacted with a compound of formula ##STR14## tocompounds with R³ meaning ##STR15## and then optionally protectinggroups are cleaved off or interesterified or the ester group ishydrolyzed or acid addition salts are formed or isomers are separated.

The introduction of substituent R^(A) according to process variant a)takes place according to the usual methods of etherification, which aredescribed, for example, in EP-A-237 467.

Reactive compound R^(A) --Y, in which Y means, for example, halogen,tosylate, mesylate or triflate, is reacted in the presence of a basesuch as alkaline-earth or alkali-alcoholate or -hydroxide, alkali oralkaline-earth carbonate in polar solvents, such as dimethylsulfoxide,dimethylformamide, acetonitrile or alcohols at room temperature orincreased temperature, optionally in the presence of phase transfercatalysts.

The introduction of substituent R³ meaning --CO--R² according to processvariant b) takes place according to the methods described in WO91/09858. For example, a β-carboline-3-carboxylic acid-alkyl esterderivative or its reactive acid derivative, such as carboxylic acidimidazolide, is reacted with a lithium-organic compound R² Li in aproticpolar solvents, such as cyclic or acyclic ethers or hydrocarbons attemperatures of -70° C. up to room temperature. Suitably, a protectinggroup can be present in 9-position of the β-carboline such as tosyl,mesyl or a trialkylsilyl group, which is cleaved off in the working upof the reaction mixture or thereafter in the usual way depending on thetype of protecting group.

The cycloaddition of compounds of formulas IV and VI according toprocesses c) and d) takes place according to the methods described inEP-A-305 322. The addition is performed at temperatures of 0° C.-40° C.in an aprotic solvent, such as aliphatic or cyclic ethers, halogenatedhydrocarbons, dimethylformamide, i.a. β-Carboline derivatives protectedin 9-position optionally can be used in the reaction. The protectinggroup is cleaved off in the usual way with the working up of thereaction mixture or thereafter by treatment with bases or acidsdepending on the type of protecting group.

The production of the nitrile oxides takes place, for example, byreaction of β-carboline-3-carbaldehydes to the corresponding oximes,which can be converted, for example, with N-halogen-succinimide,tert-butoxychloride or Na-hypochlorite in the above-mentioned aproticsolvents to hydroxamic acid halides. With bases such as Na- orK-alcoholates, trialkylamines, Hunig base, DBU or diazabicyclooctane,hydrogen halide is cleaved off from the hydroxamic acid halides andnitrile oxides are obtained, which are subjected to the cycloadditionwithout isolation (R. Annunziata et al., J. Chem. Soc. 1987, 529).

The introduction of the oxadiazole radicals according to processvariants e) and f) can take place according to the methods described inEP-161 574. The production of 1,2,4-oxadiazol-3-yl-carbolines takesplace, for example, by reaction of β-carboline-3-carboxamide oximes withacid anhydrides (R⁵ CO)₂ O at room temperature up to boiling temperatureof the mixture.

To introduce the 1,2,4-oxadiazol-5-yl radical, theβ-carboline-3-carboxylic acid or its reactive acid derivative, such ashalide, imidazolide or mixed anhydride or carboxylic acid alkyl ester isreacted in the presence of alcoholate with an amide oxime ##STR16## inaprotic solvents such as hydrocarbons, such as toluene, ethers ordimethylformamide at room temperature or increased temperature.

If an interesterification is desired, the methods described in EP-A-237467 can be used by being interesterified with alkali alcoholates or thecorresponding alcohol, optionally by adding titanium-tetra-isopropylateas catalyst at increased temperature. The introduction of the tert-butylester group takes place, e.g., by reaction of carboxylic acid withtert-butoxy-bis-dimethyl-aminomethane. The hydrolysis of the ester groupcan take place as acid or alkaline in the usual way, for example, withNa- or K-hydroxide in protic solvents or according to the processesdescribed in EP-A-161 574.

The mixtures of isomers can be separated according to the usual methodssuch as, for example, crystallization, chromatography or salt formationin the diastereomers or enantiomers.

For the formation of physiologically compatible acid addition salts, acompound of formula I is dissolved, for example, in a little alcohol andmixed with a concentrated solution of the desired acid.

Insofar as the production of the initial compounds is not described, thelatter are known or can be produced analogously to known compounds orprocesses described here from known or routinely preparable startingmaterials.

For example, the production of 3-carboxylic acid esters of formula II isdescribed in EP-A-130 140.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, limitative of the remainder of the disclosure in any waywhatsoever.

In the foregoing and in the following examples, all temperatures are setforth uncorrected in degrees Celsius and unless otherwise indicated, allparts and percentages are by weight.

The entire disclosures of all applications, patents and publications,cited above and below, and of corresponding application German P 41 18741.5, filed Jun. 5, 1991, are hereby incorporated by reference.

EXAMPLES Example 16-(1-Isoquinolyloxy)-4-methoxymethyl-β-carboline-3-carboxylic acidisopropyl ester

1.3 g of potassium hydroxide powder is added to 25 ml of dimethylsulfoxide at room temperature. Then, 3.14 g of6-hydroxy-β-carboline-3-carboxylic acid isopropyl ester is added inportions to the batch and then a solution of 2 g of 1-chloroisoquinolinein 2 ml of dimethyl sulfoxide is instilled. After 3 hours of heating toa bath temperature of 90°-95° C., 375 mg of 1-chloroisoquinoline isadded once more and heated for 2 hours to 100° C. It is poured on ice,adjusted to pH 5 with glacial acetic acid, the precipitate is suctionedoff and rewashed with ethyl acetate. This residue is chromatographed onsilica gel with methylene chloride:ethanol=13:1 as eluant. Afterconcentration by evaporation of the correspondingly combined fractionsand recrystallization, 2.5 g (55% of theory) of6-(1-isoquinolyloxy)-4-methoxymethyl-β-carboline-3-carboxylic acidisopropyl ester of melting point 10° C. is obtained.

In an analogous way, there are produced:

6-(4-Quinolyloxy)-4-methoxymethyl-β-carboline-3-carboxylic acidisopropyl ester, melting point 165°-167° C.

6-(4-methyl-2-quinolyloxy)-4-methoxymethyl-β-carboline-3-carboxylic acidisopropyl ester, melting point 174°-176° C.

6-(2-quinolyloxy)-4-methoxymethyl-β-carboline-3-carboxylic acidisopropyl ester, melting point 108° C.

6-(3-chloro-2-quinoxalyloxy)-4-methoxymethyl-β-carboline-3-carboxylicacid isopropyl ester, melting point 223°-228° C.

5-(1-isoquinolyloxy)-4-methoxymethyl-β-carboline-3-carboxylic acidisopropyl ester, melting point 235°-237° C.

6-(5-tosyl-2-pyridyloxy)-4-methoxymethyl-β-carboline-3-carboxylic acidisopropyl ester, melting point 206°-207° C.

6-(2-tosyl-5-pyridyloxy)-4-methoxymethyl-β-carboline-3-carboxylic acidisopropyl ester, melting point 206°-207° C.

6-(5-bromo-2-pyrazinyloxy)-4-methoxymethyl-β-carboline-3-carboxylic acidisopropyl ester, melting point 180°-181° C.

6-(5-bromo-2-pyrazinyloxy)-4-methoxymethyl-β-carboline-3-carboxylicacid-tert-butyl ester, melting point 195°-196° C.

6-(2-methylmercapto-4-pyrimidinyloxy)-4-methoxymethyl-β-carboline-3-carboxylicacid-isopropyl ester, melting point 209°-210° C.

6-(2-methylsulfonyl-4-pyrimidinyloxy)-4-methoxymethyl-β-carboline-3-carboxylicacid-isopropyl ester, melting point 178°-179° C.

6-(5-trifluoromethyl-2-pyridyloxy)-4-methoxymethyl-β-carboline-3-carboxylicacid-isopropyl ester, melting point 215°-216° C.

6-(4,6-dimethoxy-2-pyrimidinyloxy)-4-methoxymethyl-β-carboline-3-carboxylicacid-isopropyl ester, melting point 130°-132° C.

6-(5-bromo-2-pyrimidinyloxy)-4-methoxymethyl-β-carboline-3-carboxylicacid-isopropyl ester, melting point 211°-212° C.

6-(4,6-dimethyl-2-pyrimidinyloxy)-4-methoxymethyl-β-carboline-3-carboxylicacid-isopropyl ester, melting point 84°-85° C.

6-4,6-bis(methylthio)-1,3,5-triazin-2-yloxy!-4-methoxymethyl-β-carboline-3-carboxylicacid-isopropyl ester, melting point 167°-170° C.

6-(2,6-dimethoxy-4-pyrimidinyloxy)-4-methoxymethyl-β-carboline-3-carboxylicacid-isopropyl ester, melting point 159°-161° C.

6-(4,6-dimethoxy-1,3,5-triazin-2-yloxy)-4-methoxymethyl-β-carboline-3-carboxylicacid-isopropyl ester, melting point 159°-162° C.

6-(1,3,5-triazin-2-yloxy)-4-methoxymethyl-β-carboline-3-carboxylicacid-isopropyl ester, melting point 168°-170° C.

6-(5-methyl-2-pyrazinyloxy)-4-methoxymethyl-β-carboline-3-carboxylicacid-isopropyl ester, melting point 180° C.

6-(5-methyl-2-pyrazinyloxy)-4-methoxymethyl-β-carboline-3-carboxylicacid-tert-butyl ester, melting point 196° C.

6-(5-methyl-2-pyrazinyloxy)-3-(5-methoxymethyl-3-isoxazolyl)-4-methoxymethyl-β-carboline,melting point 194°-196° C.

6-(5-methylpyrazine-2-yl)-oxy-4-ethyl-β-carboline-3-carboxylicacid-isopropyl ester, melting point 175°-177° C.

6-(5-bromopyrazine-2-yl)-oxy-4-ethyl-β-carboline-3-carboxylicacid-isopropyl ester, melting point 227°-228° C.

6-(5-bromopyrazine-2-yl)-oxy-4-methyl-β-carboline-3-carboxylicacid-isopropyl ester, melting point 245°-246° C.

6-(6-methoxypyridine-2-yl)-oxy-4-methoxymethyl-β-carboline-3-carboxylicacid-isopropyl ester, melting point 92°-99° C.

6-(5-chloropyridazine-2-yl)-oxy-4-methoxymethyl-β-carboline-3-carboxylicacid-isopropyl ester, melting point 223° C.

6-(5-chloropyridazine-2-yl)-oxy-4-methoxymethyl-β-carboline-3-carboxylicacid-tert-butyl ester, melting point 197° C.

6-(6-methoxypyridine-2-yl)-oxy-4-methoxymethyl-β-carboline-3-carboxylicacid-tert-butyl ester, melting point 166° C.

5-(5-trifluoromethylpyridine-2-yl)-oxy-4-methoxymethyl-β-carboline-3-carboxylicacid-isopropyl ester, melting point 206° C.

5-(5-trifluoromethylpyridine-2-yl)-oxy-4-methoxymethyl-β-carboline-3-carboxylicacid-tert-butyl ester, melting point 178°-180° C.

Example 26-(1-Isoquinolyloxy)-4-methoxymethyl-3-(5-methoxymethylisoxazol-3-yl)-.beta.-carboline

330 mg of 6-(1-isoquinolyloxy)-4-methoxymethyl-β-carboline-3-carboxylicacid isopropyl ester is mixed in 10 ml of toluene with 0.62 ml oftriethylamine and 0.2 chlorotrimethylsilane and heated for 45 minutes toa bath temperature of 50°-60° C. After concentration by evaporation toabout 6 ml, it is cooled to -78° C. under argon and 1.25 ml of a 1.2molar diisobutyl aluminum hydride is instilled in hexane. After 30minutes at -78° C., it is mixed with 3 ml of ethanol and 0.75 ml of 1NNaOH. It is mixed with ethyl acetate and very little water. The organicphase is separated and concentrated by evaporation without drying. Theresidue is mixed with hexane and yields 440 mg of6-(1-isoquinolyloxy)-4-methoxymethyl-β-carboline-3-carbaldehyde. 254 mgof it is mixed in 2.5 ml of dimethylfuran with 67.5 mg of hydroxylaminehydrochloride and 69 mg of potassium hydroxide powder and allowed tostand for 16 hours at room temperature. The batch is poured on ice andthe precipitate is suctioned off and rewashed with water. 133 mg of6-(1-isoquinolyloxy-4-methoxymethyl-β-carboline-3-carbaldehyde oxime ofmelting point 215°-218° C. is obtained.

450 mg of this oxime is dissolved in 7 ml of dimethylformamide andstirred with 218 mg of N-bromosuccinimide for 30 minutes at roomtemperature. After adding 0.8 ml of triethylamine and 0.16 ml of methylpropargyl ether, it is stirred for 3 hours at room temperature. Afterconcentration by evaporation, it is dispersed in ethyl acetate/water andthe organic phase is dried, filtered and concentrated by evaporation.The residue is chromatographed twice on silica gel first with methylenechloride:ethanol=10:1 and then with methylene chloride:ethanol=12:1.After recrystallization of the corresponding fractions that are combinedand concentrated by evaporation, 200 mg of6-(1-isoquinolyloxy)-4-methoxymethyl-3-(5-methoxymethylisoxazol-3-yl)-.beta.-carbolineof melting point 107°-112° C. (ethyl acetate/hexane) is obtained.

Example 3 6-(1-Isoquinolyloxy)-4-methoxymethyl-3-benzoyl-β-carboline

476 mg of6-(1-isoquinolyloxy)-4-methoxymethyl-9-tosyl-β-carboline-3-carboxylicacid isopropyl ester is mixed in 10 ml of tetrahydrofuran under argon at-60° C. with 0.79 ml of a 0.9 m solution of phenyllithium in benzene.After 1 hour at -60° C., it is stirred for 16 hours at room temperature.The batch is acidified with glacial acetic acid and concentrated byevaporation. The residue is dispersed in ethyl acetate/water and theorganic phase is washed, dried, filtered and concentrated by evaporationin succession with respectively saturated sodium bicarbonate and commonsalt solution. The residue is chromatographed on silica gel withmethylene chloride: ethanol=10:1. The corresponding fractions arecombined, concentrated by evaporation and recrystallized. 30 mg of6-(1-isoquinolyloxy)-4-methoxymethyl-3-benzoyl-β-carboline of meltingpoint 159°-160° C. (ethyl acetate/hexane) is obtained.

The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

What is claimed is:
 1. A compound of formula I ##STR17## in which R^(A)is a triazine optionally substituted with 1 or 2 of halogen, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ alkylthio, trifluoromethyl or SO₂ --R¹, or is a5-membered heteroaromatic ring with 1 or 2 nitrogen atoms substitutedwith 1 or 2 of halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio,trifluoromethyl or SO₂ --R¹, or is a 6-membered heteroaromatic ringselected from pyridine, pyrimidine, pyrazine, or pyridazine, substitutedonce or twice with alkoxy, alkylthio, CF₃, and SO₂ R¹,R¹ is C₁₋₄ alkylor phenyl optionally substituted 1-2 times with C₁₋₄ alkyl, wherein thesubstituent on R^(A) is not halogen when R^(A) is pyridine, R⁴ ishydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₂, alkyl R³ is --CO₂ --C₁₋₆ alkyl,--CO--R², --CO₂ H, ##STR18## and R² is C₁₋₄ alkyl, C₃₋₇ cycloalkyl; C₇₋₉bicycloalkyl or a monocyclic or bicyclic C₆₋₁₂ aryl radical optionallysubstituted with C₁₋₄ alkyl, C₁₋₄ alkoxy or amino, R^(a) and R^(b) arethe same or different and each is hydrogen, C₁₋₆ alkoxy, C₁₋₆ alkyl,--CH₂ --O--C₁₋₄, alkyl, phenyl or benzyl, R^(c) and R^(d) each ishydrogen or together form a bond, and R⁵ is hydrogen, C₁₋₄ alkyl or C₃₋₇cycloalkyl, or an isomer thereof or a pharmaceutically acceptable acidaddition salt thereof. 2.6-(5-tosyl-2-pyridyloxy)-4-methoxymethyl-β-carboline-3-carboxylic acidisopropylester,6-(2-tosyl-5-pyridyloxy)-4-methoxymethyl-β-carboline-3-carboxylicacid isopropyl ester,6-(2-methylmercapto-4-pyrimidinyloxy)-4-methoxymethyl-β-carboline-3-carboxylicacid-isopropyl ester,6-(2-methylsulfonyl-4-pyrimidinyloxy)-4-methoxymethyl-β-carboline-3-carboxylicacid-isopropyl ester,6-(5-trifluoromethyl-2-pyridyloxy)-4-methoxymethyl-β-carboline-3-carboxylicacid-isopropyl ester,6-(4,6-dimethoxy-2-pyrimidinyloxy)-4-methoxymethyl-β-carboline-3-carboxylicacid-isopropyl ester,6-(4,6-dimethyl-2-pyrimidinyloxy)-4-methoxymethyl-β-carboline-3-carboxylicacid-isopropyl ester, 6-4,6-bis(methylthio)-1,3,5-triazin-2-yloxy!-4-methoxymethyl-β-carboline-3-carboxylicacid-isopropyl ester,6-(2,6-dimethoxy-4-pyrimidinyloxy)-4-methoxymethyl-β-carboline-3-carboxylicacid-isopropyl ester,6-(4,6-dimethoxy-1,3,5-triazin-2-yloxy)-4-methoxymethyl-β-carboline-3-carboxylicacid-isopropyl ester,6-(1,3,5-triazin-2-yloxy-4-methoxymethyl-β-carboline-3-carboxylicacid-isopropyl ester,6-(6-methoxypyridine-2-yl)-oxy-4-methoxymethyl-β-carboline-3-carboxylicacid-isopropyl ester,6-(6-methoxypyridine-2-yl)-oxy-4-methoxymethyl-β-carboline-3-carboxylicacid-tert-butyl ester,5-(5-trifluoromethylpyridine-2-yl)-oxy-4-methoxymethyl-β-carboline-3-carboxylicacid-isopropyl ester, or5-(5-trifluoromethylpyridine-2-yl)-oxy-4-methoxymethyl-β-carboline-3-carboxylicacid-tert-butyl ester.
 3. A compound of claim 1, wherein R³ is --CO₂--C₁₋₆ alkyl, --CO--R² wherein R² is a C₃₋₇ cycloalkyl or an optionallysubstituted phenyl radical or isoxazol-3-yl radical.
 4. A pharmaceuticalcomposition comprising an effective amount of a compound of claim 1 anda pharmaceutically acceptable carrier.
 5. A method of treating epilepsyor anxiety comprising administering to a patient in need of an effectiveamount of a compound of claim 1.